Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases with a global rising prevalence, which is closely associated with a high-fat diet (HFD) intake. Macroautophagy/autophagy is an evolutionarily conserved degradation process for cytosolic macromolecules and damaged organelles. The potential role of autophagy in hepatic lipid metabolism has been recognized, while dysfunction of hepatic autophagy has been found to contribute to NAFLD. Herein, we provide an overview of the autophagy phases with the regulatory machinery, and the current understanding of hepatic autophagy in its protective role in HFD-induced NAFLD. We also discuss the genetic and pharmacological interventions that may help elucidate the molecular mechanisms of autophagy and influence the future therapeutic direction in NAFLD.

Abbreviations

ACOX1: acyl-CoA oxidase 1; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADIPOQ: adiponectin, C1Q and collagen domain containing; ATG: autophagy related; BECN1: beclin 1; CRTC2: CREB regulated transcription coactivator 2; ER: endoplasmic reticulum; F2RL1: F2R like trypsin receptor 1; FA: fatty acid; FOXO1: forkhead box O1; GLP1R: glucagon like peptide 1 receptor; GRK2: G protein-coupled receptor kinase 2; GTPase: guanosine triphosphatase; HFD: high-fat diet; HSCs: hepatic stellate cells; HTRA2: HtrA serine peptidase 2; IRGM: immunity related GTPase M; KD: knockdown; KDM6B: lysine demethylase 6B; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAP: LC3-associated phagocytosis; LDs: lipid droplets; Li KO: liver-specific knockout; LSECs: liver sinusoidal endothelial cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MED1: mediator complex subunit 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NFE2L2: NFE2 like bZIP transcription factor 2; NOS3: nitric oxide synthase 3; NR1H3: nuclear receptor subfamily 1 group H member 3; OA: oleic acid; OE: overexpression; OSBPL8: oxysterol binding protein like 8; PA: palmitic acid; RUBCNL: rubicon like autophagy enhancer; PLIN2: perilipin 2; PLIN3: perilipin 3; PPARA: peroxisome proliferator activated receptor alpha; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; RAB: member RAS oncogene family; RPTOR: regulatory associated protein of MTOR complex 1; SCD: stearoyl-CoA desaturase; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1;SREBF2: sterol regulatory element binding transcription factor 2; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; TAGs: triacylglycerols; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VMP1: vacuole membrane protein 1.

KEYWORDS:

• Autophagy
• hepatocyte
• high-fat diet
• lipophagy
• non-alcoholic fatty liver disease
• non-parenchymal cells

Acknowledgements

We thank Qiannan Ren who contributed to searching of the literatures, drafting, reviewing and revising of the manuscript, Qiming Sun who contributed to reviewing and revising of the manuscript, and Junfen Fu who contributed to conceptualization, supervision, reviewing and revising for important intellectual content. We also thank Figdraw (www.figdraw.com) for expert assistance in the pattern drawing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The work was supported by the National Key Research and Development Program of China [No. 2021YFC2701901, No. 2016YFC1305301]; National Natural Science Foundation of China [No. 81570759, No. 81270938]; Ministry of Science and Technology of the People’s Republic of China [No. 2021YFC2700901]; National Natural Science Foundation of China [No. 32025012, No. 92254307, No. 31970695].